Pancreatic cancer is a devastating disease, causing an estimated 33,370 deaths per year in the USA with a five-year survival rate of only 5%. The molecular hallmark of this cancer is an activating mutation in the small GTPase KRas, which is well known to promote tumorigenesis. Unfortunately, it has been difficult to pharmacologically inhibit KRas, prompting us to identify druggable proteins required for KRas oncogenesis. We found that oncogenic KRas, through activation of AKT, stimulates the enzyme endothelial Nitric Oxide Synthase (eNOS). Moreover, knockdown of eNOS in human pancreatic cancer cell lines or genetic ablation of the eNOS gene in mice retarded oncogenic Ras-driven tumor growth. Small molecular weight inhibitors of NOS enzymes have been tested in phase I to III clinical trials of septic and cardiogenic shock. Capitalizing on the development of NOS inhibitors for the treatment of other diseases, we tested and found that the NOS inhibitor L-NAME impeded tumor growth of human pancreatic cancer cell lines. We propose to now test the two most developed general NOS inhibitors, L- NAME and L-NMMA, for anti-tumor activity. Both these drugs are very easy to administer, being orally available, and have been studied in mice, large mammals and humans. We will use two well established mouse models of pancreatic cancer to test the anti-tumor activity of these two NOS inhibitors: human pancreatic cancer xenografts (aim 1) as such cells are derived from human cancers, an important consideration as oncogenic Ras signaling can differ between human and rodent cells;and pancreatic expressed-oncogenic KRAS transgenic mice (aim 2), which better reflect the establishment of pancreatic cancer in the correct organ. Together, these two very different models will allow us to determine how broadly and under what conditions L- NAME and L-NMMA impede pancreatic tumorigenesis. These studies should, in turn, lay the preclinical groundwork for a potential clinical trial. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is one of the most deadliest cancers with very few therapeutic options. We discovered the enzyme eNOS is required for pancreatic tumor growth and can be pharmacologically inhibited with available small molecular weight inhibitors. The studies proposed to test NOS inhibitors for anti-tumor activity thus have important relevance to human health, specifically as possible new treatment modalities for pancreatic cancer.